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Abstract

Idiopathic pulmonary fibrosis is a rare, life threatening disease characterized by
an anarchic fibrogenesis, limited survival and few therapeutic options. Its pathogenesis
is complex and involves the interaction among various pathways driven by proinflammatory/profibrogenetic
mediators such as platelet -derived growth factor, vascular endothelial growth factor
or basic fibroblast growth factor. Given their prominent pathogenic roles in this
disease such growth factor might be suitable therapeutic targets.In fact, the existing
preclinical and clinical data demonstrated that their therapeutic inhibition results
in a delayed progression of the pulmonary fibrosis and in the improvement of the disease
outcome. BIBF 1120 is a potent triple blocker of the receptors of these growth factors
which is currently evaluated as a potential therapy in the idiopathic pulmonary fibrosis.
This review discusses the existing data supporting its potential use in this disease.

Keywords:

Review

Idiopathic pulmonary fibrosis (IPF) is a rare life-threatening disease of the lungs
characterized by a rapidly progressive fibrogenesis, limited survival and by limited
therapeutic resources. The poor disease outcome is due not only to the fact that there
are only few therapies available, but also to the rather modest antifibrotic effects
of treatments such as corticosteroids, cyclophosphamide or azathioprine which are
conventionally used as the first line approach in such patients [1]. More recently, pirfenidone, was approved as the first antifibrotic therapy for IPF
based on demonstrated sustained clinical efficacy [2]. Other investigational drugs are currently assessed in the same setting and these
include anticoagulant agents, anti growth factors agents or antioxidant molecules.
Growth factor antagonists in particular are of promise due to their potent antifibrotic
effects demonstrated in other similar settings [3,4].

BIBF 1120 is a triple tyrosin kinase inhibitor and a potent antagonist of growth factors
such as platelet-derived growth factor, vascular endothelial growth factor and basic
fibroblast growth factor, and it is currently evaluated in clinical trials as a potential
IPF therapy.

This paper summarizes the rationale of its use in this disease based on existing evidence.

Scientific rationale of tyrosin kinases inhibition in the IPF

Mediators such as platelet-derived growth factor (PDGF), vascular-endothelial growth
factor (VEGF) and basic fibroblast growth factor (bFGF) are currently individually
or collectively investigated as potential therapeutic targets for diseases such as
cancers, pulmonary hypertension or idiopathic pulmonary fibrosis. VEGF, PDGF or FGF
are now known mitogenic factors playing major pathogenic roles in tumour angiogenesis,
extracellular matrix proliferation and fibrogenesis [5]. VEGF for example was found to be over expressed by tumour cells in response to tissue
hypoxemia and was reported to increase proliferation and migration of the endothelial
cells and to inhibit their apoptosis [6,7]. PDGF is another growth factor which was found to be involved in the pathogenesis
of various proliferative disorders such as tumours, or pulmonary fibrosis in which
it was found to stimulate proliferation of smooth muscle cells as well as fibrogenesis
[6,8]. In a mouse model of silica-exposure-induced lung fibrosis, PDGF-BB was found to
be over expressed via a TGF-β-mediated autocrine pathway [8].

bFGF was demonstrated to induce proliferation of smooth muscle cells, myofibroblasts,
and fibroblasts and its expression was found to be up regulated in IPF [7].

Given the potent mitogenic effects of these growth factors, their inhibition is expected
to reduce the angiogenesis and the fibrosis and in fact such effects are already used
in cancer therapy and evaluated in various forms of cancer as well as in other diseases
such as pulmonary fibrosis or IPF [9].

The inhibition of such factors can be achieved via different approaches, the most
used and evaluated currently being the related receptors inhibition. VEGFR, PDGFR
and bFGFR are tyrosine kinases which become activated upon ligand binding and stimulate
the downstream signaling pathways [5].

Imatinibmesylate, another tyrosin kinase inhibitors which acts specifically on PDGF
was initially evaluated for its potential antifibrotic effects in preclinical and
clinical studies. In experimental studies imatinib was found to inhibit fibroblast
proliferation, and collagen deposition in vitro and in vivo[10].

When evaluated in a clinical study in patients with IPF, imatinib given once daily
at a dosage of 600 mg/day, for 96 weeks demonstrated no significant benefit over placebo
in slowing disease progression or lung function impairment [11].

However, the multiple inhibition of such growth factors might be associated with a
more potent antifibrotic effect: in a preclinical study performed in the mice model
of bleomycin-induced pulmonary fibrosis, BIBF 1000 a triple kinase inhibitor for the
PDGFR, VEGFR and bFGFR was found to attenuate bleomycin-induced lung fibrogenesis
by reducing the expression of the pro-fibrogenetic factors and by decreasing the collagen
lung content [12]. In a an ex vivo assay performed on human bronchial fibroblasts BIBF 1000 inhibited
TGF-β-induced myofibroblast differentiation [12].

BIBF 1120 (nintedanib), an oxindole derivative is a triple kinase inhibitor with potent
suppressing effects on VEGFR, PDGFR and bFGFR [9]. Nintedanib is currently in advanced clinical testing for various types of advanced
solid cancers as a potential antiangiogenic therapy to be added to the cytotoxic agents
to exert synergistic antitumour effects. The antiangiogenic effects of nintedanib
were demonstrated in various preclinical studies such including inhibition of proliferation
of HUVEC cell line or animal models of xenografttumour, as well as in clinical trials
in subjects with advanced non-small cell lung cancer or gastrointestinal tumours [9].

Clinical data with BIBF1120 in IPF

BIBF 1120 was assessed in many clinical studies performed in a wide range of solid
malignancies including non-small cell lung cancer (NSCLC) as an antiangiogenic therapy
and in few clinical studies as a potential antifibrotic therapy in IPF [9].

Patients aged at least 40 years with a predefined IPF diagnosis of less than 5 years
prior to the study screening were included in the study. Eligible patients had a FVC≥50%
and a DLCOpred 30-79% and a PaO2 ≥55mmHg. Concomitant oral therapy with prednisone (or equivalents) of ≤15 mg if stable
during the 8 weeks previous to the study enrollment [13].

The primary efficacy endpoint was represented by the FVC decline rate and the secondary
endpoints included changes from baseline in FVC, DLco, SpO2, TLC, exercise capacity,
SGRQ (St. George respiratory questionnaire) scores, the incidence of acute exacerbations,
overall mortality, and that due to respiratory causes.

The highest BIBF 1120 dose was associated with the most significant therapeutic effect
on the lung function decline compared to placebo, the drug reducing the annual rate
of lung function decline by 68.4% compared to placebo group.

The highest dose of BIBF 1120 therapy was also associated with a lower percentage
of patients exhibiting a significant reduction of the FVC (of >10% or of >200ml) compared
to placebo (23.8% versus 44%, p=0.004). Unlike placebo BIBF 1120 preserved the total
lung capacity (−0.24 liters vs. 0.12 liters, p<0.001).

Mean change from baseline in the SpO2 was −0.2% with BIBF 1120 and −1.3% with placebo (p = 0.02). The highest dose therapy
was also associated with a lower percentage of significant desaturation (>4% reduction
from baseline in resting SpO2) over the study period 3.6% respectively 11.0%, p = 0.03). BIBF 1120 didn’t exert
a significant therapeutic benefit on the DLCO and in the exercise capacity as compared to placebo.

Health Related Quality-of-Life (HRQoL) evaluated with SGRQ was found to be significantly
improved with the BIBF highest dose as compared to placebo the difference being also
clinically significant: mean change −0.66 points with the active treatment compared
to 5.46 points with placebo p = 0.007. The domain analysis demonstrated that the significant
therapeutic effect on HRQoL was due to the significant improvements in symptoms and
activity domains (−3.14 points with BIBF 1120 compared to 6.45 points with placebo,
p = 0.003 and 0.32 points with BIBF 1120 compared to 7.48 points, p = 0.004). A dose-dependent
trend toward a reduction of the score of impact domain score reduction was also reported
with the BIBF 1120. The proportion of patients with a clinically significant improvement
in the HRQoL scores was higher in the treatment arms 100 mg and 150 mg (32.6% and
29.1%, respectively) versus placebo group (16.1%; p = 0.007 and p = 0.03, respectively).
An in-depth analysis of the HRQoL and dyspnea change over baseline was also conducted.
It was found a risk of dyspnea worsening versus baseline in a comparable number (%)
of patients irrespective of the treatment allocation: 31(40.3%) in placebo arm, 31(41.3%)
with BIBF-1120 50 mg/day 31(38.3%) BIBF-1120 100 mg/day, 33(40.2%) BIBF-1120 200 mg/day,
26(34.2%) BIBF-1120 300 mg/day. For the HRQoL however, a dose dependent improvement
was demonstrated: 0.79 units with BIBF-1120 50 mg/day, 3.28 units with BIBF-1120 100
mg/day, 3.98 units with BIBF-1120 200 mg/day, 6.12 units with BIBF-1120 300 mg/day
(p=0.0071 for the highest dose versus placebo). The overall HRQoL worsening in the
placebo arm was also clinically significant (MCID 4 units of score). The most significant
therapeutic benefit was detected in the SGRQ symptoms score: 9.6 units improvement
with BIBF 1120 compared to placebo (p=0.0028). The likelihood of a clinically significant
improvement was the highest with BIBF 1120 200 mg/day, (odds ratio 2.7, p=0.0069).
Mean HRQoL change was found to correlate inversely with mean FVC change (r =0.0304,
p=0.0081) [14]. BIBF 1120 highest dose was associated with a significant reduction of the incidence
of acute exacerbations compared to placebo (2.4 versus 15.7 per 100 patient-years,
p = 0.02), and a trend towards a dose-dependent increase in the effect size with the
100 mg dose was also noted. The 150 and the 100mg BIBF1120 doses were also associated
with a trend toward a lower mortality rate compared to placebo (p = 0.04 for 100 mg
and p = 0.06 for 150 mg). No significant differences in terms of mortality rates with
the treatment groups compared to placebo were reported.

Overall, there were comparable incidences of adverse events among all groups with
comparable rates of severe/life-threatening effects as well. The adverse events which
most commonly led to treatment discontinuation were diarrhea, nausea, and vomiting
and were reported in the group receiving 150 mg twice a day [13].

The TOMORROW trial is planned to be followed by an open-label continuation phase in
which efficacy and safety of BIBF-1120 are planned to be further studied [15].

Two phase III studies aimed at evaluating the efficacy and safety of BIBF 1120 150
mg×2/day over 52 weeks in patients with IPF are also planned. These two studies have
similar endpoints which include the annual decline rate in FVC, quality of life and
time to first exacerbation, overall survival [16].

Conclusions

IPF is a debilitating disease associated with a limited life span and characterized
by an anarchic, rapidly progressing fibrogenesis. The pathogenesis of the IPF is complex
and involves the interaction of multiple mediator-driven pathways having as common
(up) regulator the TGF-β and including growth factors such as PDGF, bFGF or VEGF.
The preclinical and clinical data demonstrated that the concomitant inhibition of
such factors with compounds such as BIBF 1120 is able to slow the progression of lung
fibrosis and to improve the disease outcome. However further clinical data are needed
to better document the clinical efficacy and safety of BIBF 1120 and to better position
this potential therapy in the IPF management.